The present invention relates to a multistage contraceptive preparation based on natural estrogens.
Oral contraceptives were first marketed 60 years ago. By continuous research it has been possible to reduce the required dosages of hormones in a stepwise manner. Currently low dosage oral contraceptives exist which chiefly comprise an estrogen component and a gestogen component. The hormone dosage of these contraceptives is delivered in different combinations and dosages in the form of combination preparations (one-stage preparation) or multistage combination preparations (staged preparations) and sequenced preparations (two-stage preparations) over time periods of from 21 to 28 days.
One-stage preparations (usually designated as combination preparations) are characterized by a constant dosage of certain estrogens and gestogens each day. Because of the uniform delivery of gestogen ingredients with estrogen components from the first application day, the combination preparation is a highly reliable contraceptive.
The ovulatory LH-peak is reliably suppressed with all forms of combination preparation so that both ovulation and Corpus luteum formation are suppressed (M. Elstein, et al, “Studies on low dose oral contraceptives: cervical mucus and plasma hormone changes in relation to circulating d-nogestrel and 17-ethinyl estradiol concentrations”, in Fertil Steril. 27, p. 892, 1976; Kontrazeption mit Hormonen (trans: Contraception with Hormones), H. D. Taubert and H. Kuhl, eds., Georg Thieme Verlag, Stuttgart/New York, 1965). Of course early secretion changes of the still weakly developing endometrium can cause intervening bleeding above all in the first cycle under the influence of a gestogen.
Modified combination or multistage preparations currently include two-stage preparations and three-stage preparations. Two-stage preparations are those, which contain a gestogen dosage, which is reduced in comparison to the conventional combination preparation, which is increased in the second stage (cycle half). A stage with a lowered gestogen dosage lasting for 11 days follows in a 21/22 day pill regime, while the estrogen dosage remains the same over the administration period.
Three-stage preparations contain lowered gestogen dosages as well as lowered estrogen dosages in the first delivery stage, which increases in two stages to its highest gestogen dosage in the last 7 to 10 days, while the estrogen ingredient is increased either uniformly or briefly during the middle of the cycle over a duration of 5 to 6 days analogously to the normal physiological cycle. Three-stage preparations allow the entire dosage of gestogens to be maintained at a lower lever than in other oral contraceptives (L. Carlborg, “Comparison of contraceptive acceptability of levonorgestrel and ethinyl oestradiol administered in a three-stage (trionetta) and a one-stage (neoletta) version”, in Contraception 27, p. 5, 1983).
Two-staged preparations (sequenced preparations) contain a pure estrogen component in the first 7 to maximum 11 days of use and additionally a gestogen ingredient in the following 10 to 14 days. Because of that the endometrium is subjected to changes which very closely correspond to the normal physiological cycle. They therefore provide very good cycle control. Sequence preparations lower the basal gonadotropin level in a manner similar to combination preparations, in which the FSH-level is more strongly suppressed or lowered than the LH-level (K.AKTORIES, et al, “Die Beeinflussung des Ovarialzyklus durch verschiedene Typen hormonaler Kontrazeptiva (trans: The effect of different types of hormonal contraceptives on ovarian cycles)” in Geburtshilfe Frauenheilkunde 36, P. 318, 1976).
All currently known combination preparations for oral contraception contain ethinyl estradiol or its 3-methyl ester, mestranol, as estrogen ingredient. The latter compound is a prodrug and is metabolized in the body to ethinyl estradiol. Ethinyl estradiol has, among other things, a series of disadvantages and side effects. This synthetic estrogen is rapidly resorbed in the stomach and intestinal tract, however, because it is easily metabolized, it is rapidly absorbed already in the mucous membrane of the small intestine and/or rapidly changes chemically as a result. Besides this process has large individual variations. Hence unsatisfactory and large individual differences of bioavailability of ethinyl estradiol result. Ethinyl estradiol causes suicidal blockage of the Cytochrome P-450 system (F. P. Guengerich, “Oxidation of alpha-ethinyl estradiol by human liver Cytochrome P-450”, in Molec. Pharmacol. 33, p.500, 1988; R. Bocker, et al, “In vitro interaction of contraceptive steroids with human liver Cytochrome P-450 enzymes, Advances Contraception 7, p.140, 1991) and inhibits its own metabolism. Since gestogens and a series of other foreign materials/medications in large part are converted by the same decomposition paths, the repeated application of ethinyl estradiol-containing contraceptives can lead to an accumulation of certain xenobiotics in the body. Furthermore ethinyl estradiol has carcinogenic properties (B. T. Zhu, et al, “The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their conversion to catechol metabolites” in Endocrinol. 132, p. 577, 1993).
The general administration of natural estrogens is suggested as an alternative to ethinyl estradiol in German Patent Applications DE 41 04 385 and DE 42 24 534.
A contraceptive administration system is known from U.S. Pat. No. 4,921,843, in which a placebo is taken between the last day's dosage of the second component and the first day's dosage of the first component. This contraceptive administration system has the disadvantage that follicle maturation begins during the administration of the placebos.
The sole administration of natural estrogens has currently not found a practical application. Thus H. D. Taubert and H. Kuhl (Kontrazeption mit Hormonen, H. D. Taubert and H. Kuhl, Eds., Georg Thieme Verlag, Stuttgart, New York, 1995) fail to suggest the use of natural estradiols as estrogen ingredients in oral contraceptives. While the gestogen ingredients alone provide a reliable contraceptive protection, the proliferation of the endometrium by the natural estrogen is insufficient. A bleeding anomaly such as intervening bleeding results up to the blood-free cycles.
Up to now difficulties have occurred in experiments to develop a so-called “semi-natural pill” based on natural estrogens (e.g. micronized 17β-estradiol, natural 17β-estradiol esters, conjugated estrogens, phytoestrogens and estrone, estriol and their derivatives). For example the combination of estradiol (estradiol valerate 1 mg and/or 2 mg administered for 10 and/or 11 days) and cyproterone acetate (1 mg and/or 2 mg for 10 to 11 days) caused 33% intervening bleeding (E. HIRVONEN, et al, in “Oral Contraceptive-containing natural estradiol for premenopausal women”, in Maturitas 21, p. 27, 1995) or the combination of estradiol (3 mg) and desogestrel (0.150 mg) for 21 days caused 30% intervening bleeding (H. Coelingh Bennink, “Research in Contraception”, 10th Congress of the European Association of Gynecologists and Obstetricians, 1995).
Preliminary experiments for the instant invention were performed with constant estradiol dosages over 28 days and constant gestogen dosages over 24 days as well as with different estradiol dosages (2.0 mg, 4.0 mg and 2.0 mg over 7, 14 and 7 days respectively) and constant gestogen dosages over 21 days. These studies failed because the intervening bleeding rate of 25% was not substantially different from that already known from the studies of E. Hirvonen and H. Coelingh Bennink (E. Schleussner, Jenapharm GmbH Report, 1995).